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Role of Cannabinoids in the Management of Neuropathic Pain

CNS Drugs volume 22, pages 645–653 (2008)Cite this article

Abstract

The treatment of pain, particularly neuropathic pain, is one of the therapeutic applications of cannabis and cannabinoids that is currently under investigation and that stimulates interest among clinicians and basic researchers.

Animal pain models, including models of acute, antinociceptive, inflammatory and neuropathic pain, have demonstrated the antinociceptive efficacy of cannabinoids without causing serious alterations in animal behaviour. These data, together with the historic and current empiric use of cannabinoids, support the interest in the analysis of their effectiveness in treating neuropathic pain.

The evaluation of controlled trials that focus on the effect of cannabinoids on neuropathic pain reveals that this class of drugs is able to significantly reduce pain perception. Nevertheless, this effect is generally weak and clinical relevance remains under evaluation. Moreover, there is a lack of controlled trials and, in particular, comparisons with other drugs generally used in the treatment of neuropathic pain.

Despite the fact that further research is required to achieve a definitive assessment, current data obtained from basic research and from analysis of the available controlled trials indicate that cannabinoids can be accepted as a useful option in the treatment of neuropathic pain.

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Table I
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References

  1. Mechoulam R. The pharmacohistory of cannabis sativa. In: Mechoulam R, editor. Cannabinoids as therapeutic agents. Boca Raton (FL): CRC Press, 1986: 1–20

    Google Scholar 

  2. Reynolds JR. Therapeutical uses and toxic effects of Cannabis indica [letter]. Lancet 1890; 22: 637

    Article  Google Scholar 

  3. Gaoni Y, Mechoulam R. Isolation, structure and partial synthesis of an active constituent of hashish. J Am Chem Soc 1964; 86: 1646–7

    Article  CAS  Google Scholar 

  4. Devane WA, Dysarz FA, Johnson MR, et al. Determination and characterization of a cannabinoid receptor in rat brain. Mol Pharmacol 1988; 34: 605–13

    PubMed  CAS  Google Scholar 

  5. Matsuda LA, Lolait SJ, Brownstein MJ, et al. Structure of a cannabinoid receptor and functional expression of the cloned cDNA. Nature 1990; 346: 561–4

    PubMed  Article  CAS  Google Scholar 

  6. Devane WA, Hanus L, Breuer A, et al. Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science 1992; 258: 1946–9

    PubMed  Article  CAS  Google Scholar 

  7. Pertwee RG. The therapeutic potential of drugs that target cannabinoid receptors or modulate the tissue levels or actions of endocannabinoids. AAPS J 2005; 7(3): E625–54

    PubMed  Article  CAS  Google Scholar 

  8. Herkenham M, Lynn AB, Little MD, et al. Cannabinoid receptor localization in brain. Proc Natl Acad Sci U S A 1990; 87: 1932–6

    PubMed  Article  CAS  Google Scholar 

  9. Pertwee RG. Pharmacology of cannabinoid CB1 and CB2 receptors. Pharmacol Ther 1997; 74: 129–80

    PubMed  CAS  Google Scholar 

  10. Pertwee RG. Pharmacological, physiological and clinical implications of the discovery of cannabinoid receptors. Biochem Soc Trans 1998; 26(2): 267–72

    PubMed  CAS  Google Scholar 

  11. Skaper SD, Buriani A, Dal Toso R, et al. The ALIAmide palmitoylethanolamide and cannabinoids, but not anandamide, are protective in a delayed postglutamate paradigm of excitotoxic death in cerebellar granule neurons. Proc Nat Acad Sci U S A 1996; 93(9): 3984–9

    Article  CAS  Google Scholar 

  12. Sagan S, Venance L, Torrens Y, et al. Anandamide and WIN 55212-2 inhibit cyclic AMP formation through G-proteincoupled receptors distinct from CB1 cannabinoid receptors in cultured astrocytes. Eur J Neurosci 1999; 11(2): 691–9

    PubMed  Article  CAS  Google Scholar 

  13. Griffin G, Fernando SR, Ross RA, et al. Evidence for the presence of CB2-like cannabinoid receptors on peripheral nerve terminals. Eur J Pharmacol 1997; 339: 53–61

    PubMed  Article  CAS  Google Scholar 

  14. Calignano A, La Rana G, Giuffrida A, et al. Control of pain initiation by endogenous cannabinoids. Nature 1998; 394(6690): 277–81

    PubMed  Article  CAS  Google Scholar 

  15. Malan P, Ibrahim M, Deng H, et al. CB2 cannabinoid receptormediated peripheral antinociception. Pain 2001; 93: 239–45

    PubMed  Article  CAS  Google Scholar 

  16. Mechoulam R, Ben-Shabat S, Hanus L, et al. Identification of an endogenous 2-monoglyceride, present in canine gut, that binds to cannabinoid receptors. Biochem Pharmacol 1995; 50: 83–90

    PubMed  Article  CAS  Google Scholar 

  17. Pertwee R, Ross RA. Cannabinoid receptors and their ligands. Prostaglandins Leukot Essent Fatty Acids 2002; 66: 101–21

    PubMed  Article  CAS  Google Scholar 

  18. Howlet AC, Barth F, Bonner T, et al. International Union of Pharmacology: XXVII. Classification of cannabinoid receptors. Pharmacol Rev 2002; 54: 161–202

    Google Scholar 

  19. Goya P, Jagerovic N, Hernández-Folgado L, et al. Cannabinoids and neuropathic pain. Mini Rev Med Chem 2003; 3(7): 765–72

    PubMed  Article  CAS  Google Scholar 

  20. Hillard CJ, Jarrahian A. Cellular accumulation of anandamide: consensus and controversy. Br J Pharmacol 2003; 140: 802–8

    PubMed  Article  CAS  Google Scholar 

  21. Stella N, Schweitzer P, Piomelli D. A second endogenous cannabinoid that modulates long-term potentiation. Nature 1997; 388: 773–8

    PubMed  Article  CAS  Google Scholar 

  22. Hanus L, Abu Lafi SS, Fride E, et al. 2-Arachidonyl glyceryl ether, an endogenous agonist of the cannabinoid CB1 receptor. Proc Natl Acad Sci U S A 2001; 98: 3662–5

    PubMed  Article  CAS  Google Scholar 

  23. Porter AC, Sauer JM, Knierman MD, et al. Characterization of a novel endocannabinoid, virodhamine, with antagonist activity at the CB1 receptor. J Pharmacol Exp Ther 2002; 301: 1020–4

    PubMed  Article  CAS  Google Scholar 

  24. Huang SM, Bisogno T, Trevisani M, et al. An endogenous capsaicin-like substance with high potency at recombinant and native vanilloid VR1 receptors. Proc Natl Acad Sci U S A 2002; 99: 8400–5

    PubMed  Article  CAS  Google Scholar 

  25. Pertwee R. Cannabinoid pharmacology: the first 66 years. Br J Pharmacol 2006; 147: S163–71

    PubMed  Article  CAS  Google Scholar 

  26. Di Marzo V, De Petrocellis L, Bisogno T. The biosynthesis, fate and pharmacological properties of endocannabinoids. In: Pertwee RG, editor. Cannabinoids: handbook of experimental pharmacology. Vol. 168. Heidelburg: Springer-Verlag, 2005: 147–85

    Google Scholar 

  27. Grotenhermen F. Cannbinoids. Curr Drug Targets CNS Neurol Disord 2005; 4(5): 507–30

    PubMed  Article  CAS  Google Scholar 

  28. Buxbaum DM. Analgesic activity of delta-9-tetrahydrocannabinol in the rat and mouse. Psychopharmacologia 1972; 25: 275–80

    PubMed  Article  CAS  Google Scholar 

  29. Sofia RD, Vassar HB, Knobloch LC. Comparative analgesic activity of various naturally occurring cannabinoids in rats and mice. Psychopharmacologia 1975; 40: 285–95

    PubMed  Article  CAS  Google Scholar 

  30. Johnson MR, Melvin LS, Milne GM. Prototype cannabinoid analgetics, prostaglandins and opiate search for points of mechanistic interaction. Life Sci 1982; 31: 1703–6

    PubMed  Article  CAS  Google Scholar 

  31. Dajani EZ, Larsen KR, Taylor J, et al. 19,19-Dimethylheptyl-D-8-tetrahydrocannabinol-11-oic acid: a novel, orally effective cannabinoid with analgesic and anti-inflammatory properties. J Pharmacol Experiment Ther 1999; 291: 31–8

    CAS  Google Scholar 

  32. Pertwee RG. Cannabinoid receptors and pain. Prog Neurobiol 2001; 63: 569–611

    PubMed  Article  CAS  Google Scholar 

  33. De Vry J, Denzer D, Reissmueller E, et al. 3-[2-cyano-3-(trifluoromethyl)phenoxy]phenyl-4,4,4-trifluoro-l-butanesulfonate (BAY 59-3074): a novel cannabinoid Cbl/Cb2 receptor partial agonist with antihyperalgesic and antiallodynic effects. J Pharmacol Exp Ther 2004; 310(2): 620–32

    PubMed  Article  Google Scholar 

  34. Smith FL, Fujimori K, Lowe J, et al. Characterization of delta9-tetrahydrocannabinol and anandamide antinociception in nonarthritic and arthritic rats. Pharm Biochem Behavior 1998; 60(1): 183–91

    Article  CAS  Google Scholar 

  35. Choong KC, Su X, Urban MO. Effect of CP55,940 on mechanosensory spinal neurons following chronic inflammation. Neurosci Lett 2007; 414(2): 105–9

    PubMed  Article  CAS  Google Scholar 

  36. Vann RE, Cook CD, Martin BR, et al. Cannabimimetic properties of ajulemic acid. J Pharmacol Exp Ther 2007; 320(2): 678–86

    PubMed  Article  CAS  Google Scholar 

  37. Beaulieu P, Bisogno T, Punwar S, et al. Role of the endogenous cannabinoid system in the formalin test of persistent pain in the rat. Eur J Pharmacol 2000; 396(2–3): 85–92

    Article  CAS  Google Scholar 

  38. Guindon J, Desroches J, Beaulieu P. The antinociceptive effects of intraplantar injections of 2-arachidonoyl glycerol are mediated by cannabinoid CB2 receptors. Br J Pharmacol 2007; 150(6): 693–701

    PubMed  Article  CAS  Google Scholar 

  39. Calignano A, La Rana G, Iufrida A, et al. Control of pain initiation by endogenous cannabinoids. Nature 1998; 396: 277–81

    Google Scholar 

  40. Amaya F, Shimosato G, Kawasaki Y, et al. Induction of CB1 cannabinoid receptor by inflammation in primary afferent neurons facilitates antihyperalgesic effect of peripheral CB1 agonist. Pain 2006; 124(1-2): 175–83

    PubMed  Article  CAS  Google Scholar 

  41. Romero-Sandoval A, Eisenach JC. Spinal cannabinoid receptor type 2 activation reduces hypersensitivity and spinal cord glial activation after paw incision. Anesthesiology 2007; 106(4): 787–94

    PubMed  Article  CAS  Google Scholar 

  42. Vann RE, Cook CD, Martin BR, et al. Cannabimimetic properties of ajulemic acid. J Pharmacol Exp Ther 2007; 320(2): 678–86

    PubMed  Article  CAS  Google Scholar 

  43. La Rana G, Russo R, Campolongo P, et al. Modulation of neuropathic and inflammatory pain by the endocannabinoid transport inhibitor AM404 [N-(4-hydroxyphenyl)-eicosa-5,8,11,14-tetraenamide]. J Pharmacol Exp Ther 2006; 317(3): 1365–71

    PubMed  Article  CAS  Google Scholar 

  44. Martin WJ, Loo CM, Basbaum AI. Spinal cannabinoids are antiallodynic in rats with persistent inflammation. Pain 1999; 82(2): 199–205

    PubMed  Article  CAS  Google Scholar 

  45. Agarwal N, Pacher P, Tegeder I, et al. Cannbinoids mediate analgesia largely via peripheral type cannabioid receptors in nociceptors. Nat Neurosci 2007; 10(7): 870–9

    PubMed  Article  CAS  Google Scholar 

  46. Jeske NA, Patwardhan AM, Gamper N, et al. Cannabinoid WIN 55.212-2 regulates TRPV1 phosphorialtion in sensory neurons. J Biol Chem 2006; 281(43): 32879–90

    PubMed  Article  CAS  Google Scholar 

  47. Costa B, Trovato AE, Comelli F, et al. The non-psychoactive cannabis constituent cannabidiol is an orally effective therapeutic agent in rat chronic inflammatory and neuropathic pain. Eur J Pharmacol 2007; 556(1–3): 75–83

    PubMed  Article  CAS  Google Scholar 

  48. Besse D, Lombard MC, Besson JM. Time-related decreases in mu and delta opioid receptors in the superficial dorsal horn of the rat spinal cord following a large unilateral dorsal rhizotomy. Brain Res 1992; 578: 115–27

    PubMed  Article  CAS  Google Scholar 

  49. Hohmann AG, Herkenham M. Regulation of cannabinoid and mu opioid receptors in rat lumbar spinal cord following neonatal capsaicin treatment Neurosci Lett 1998; 252: 13–16

    CAS  Google Scholar 

  50. Farquhar-Smith WP, Egertova M, Bradbury EJ, et al. Cannabinoid CB(1) receptor expression in rat spinal cord. Mol Cell Neurosci 2000; 15: 510–21

    PubMed  Article  CAS  Google Scholar 

  51. Siegling A, Hofmann HA, Denzer D, et al. Cannabinoid CB(1) receptor upregulation in a rat model of chronic neuropathic pain. Eur Pharmacol 2001; 415: R5–7

    Article  CAS  Google Scholar 

  52. Monhemius R, Azami J, Green DL, et al. CB1 receptor mediated analgesia from the nucleus reticularis gigantocellularis pars alpha is activated in an animal model of neuropathic pain. Brain Res 2001; 908: 67–74

    PubMed  Article  CAS  Google Scholar 

  53. Zhang J, Hoffert C, Vu HK, et al. Induction of CB2 receptor expression in the rat spinal cord of neuropathic but not inflammatory chronic pain models. Eur J Neurosci 2003; 17(12): 2750–4

    PubMed  Article  Google Scholar 

  54. Bennett GJ, Xie YK. A peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in man. Pain 1988; 33(1): 87–107

    PubMed  Article  CAS  Google Scholar 

  55. Seltzer Z, Dubner R, Shir Y. A novel behavioral model of neuropathic pain disorders produced in rats by partial sciatic nerve injury. Pain 1990; 43(2): 205–18

    PubMed  Article  CAS  Google Scholar 

  56. Burchiel KJ, Russell LC, Lee RP, et al. Spontaneous activity of primary afferent neurons in diabetic BB/Wistar rats: a possible mechanism of chronic diabetic neuropathic pain. Diabetes 1985; 34(11): 1210–3

    PubMed  Article  CAS  Google Scholar 

  57. Polomano RC, Mannes AJ, Clark US, et al. A painful peripheral neuropathy in the rat produced by the chemotherapeutic drug, paclitaxel. Pain 2001; 94(3): 293–304

    PubMed  Article  CAS  Google Scholar 

  58. Tanner KD, Reichling DB, Levine JD. Nociceptor hyper-responsiveness during vincristine-induced painful peripheral neuropathy in the rat. J Neurosci 1998; 18(16): 6480–91

    PubMed  CAS  Google Scholar 

  59. Shinoda K, Hruby VJ, Porreca F. Antihyperalgesic effects of loperamide in a model of rat neuropathic pain are mediated by peripheral delta-opioid receptors. Neurosci Lett 2007; 411(2): 143–6

    PubMed  Article  CAS  Google Scholar 

  60. Choi Y, Yoon YW, Na HS, et al. Behavioral signs of ongoing pain and cold allodynia in a rat model of neuropathic pain. Pain 1994; 59(3): 369–76

    PubMed  Article  CAS  Google Scholar 

  61. Pascual D, Goicoechea C, Suardiaz M, et al. A cannabinoid agonist, WIN 55,212-2, reduces neuropathic nociception induced by paclitaxel in rats. Pain 2005; 118(1–2): 23–34

    PubMed  Article  CAS  Google Scholar 

  62. Dogrul A, Gul H, Yildiz O, et al. Cannabinoids blocks tactile allodynia in diabetic mice without attenuation of its antinociceptive effect. Neurosci Lett 2004; 368: 82–6

    PubMed  Article  CAS  Google Scholar 

  63. Wood HC. Treatise on therapeutics. Philadelphia (PA): JB Lippincott and Co., 1886

    Google Scholar 

  64. Hare HA, Chrystie W. A system of practical therapeutics. Vol. 3. Philadelphia (PA): Lee Brothers, 1892

    Google Scholar 

  65. Corey S. Recent developments in the therapeutic potential of cannabinoids. P R Health Sci J 2005; 24(1): 19–26

    PubMed  Google Scholar 

  66. Fisher B, Johnston D, Leake P. Marijuana for medicinal purposes: an evidence-based assessment. Workers’ Compensation Board of British Columbia [online]. Available from URL: http://www.worksafebc.com/health_care_providers/Assets/PDF/marijuana_medicinal_purposes.pdf [Accessed 2007 May 21]

  67. Martin CW. Efficacy of marijuana in treating chronic noncancer pain: a short review. Workers’ Compensation Board of British Columbia, Evidence Based Practice Group [online]. Available from URL: http://www.worksafebc.com/health_care_providers/Assets/PDF/marijuana_medicinal_purposes_update.pdf [Accessed 2007 May 21]

  68. Campbell FA, Tramer MR, Carroll D, et al. Are cannabinoids an effective and safe treatment option in the management of pain? A qualitative systematic review. BMJ 2001; 323(7303): 13–6

    PubMed  Article  CAS  Google Scholar 

  69. Zajicek J, Fox P, Sanders H, et al. Cannabinoids for treatment of spasticity and other symptoms related to multiple sclerosis (CAMS study): multicentre randomised placebo-controlled trial. Lancet 2003; 362(9395): 1517–26

    PubMed  Article  CAS  Google Scholar 

  70. Wade DT, Robson P, House H, et al. A preliminary controlled study to determine whether whole-plant cannabis extracts can improve intractable neurogenic symptoms. Clinical Rehab 2003; 17(1): 21–9

    Article  Google Scholar 

  71. Rog DJ, Nurmikko TJ, Friede T, et al. Randomized, controlled trial of cannabis-based medicine in central pain in multiple sclerosis. Neurology 2005; 65(6): 812–9

    PubMed  Article  Google Scholar 

  72. Svendsen KB, Jensen TS, Bach FW. Does the cannabinoid dronabinol reduce central pain in multiple sclerosis? Randomised, double-blind, placebo-controlled, crossover trial. BMJ 2004; 329(7460): 253–7

    PubMed  Article  CAS  Google Scholar 

  73. Wissel J, Haydn T, Müller J, et al. Low dose treatment with the synthetic cannabinoid nabilone significantly reduces spasticity-related pain: a double-blind placebo-controlled cross-over trial. J Neurol 2006; 253(10): 1337–41

    PubMed  Article  CAS  Google Scholar 

  74. Berman JS, Symonds C, Birch R. Efficacy of two cannabis based medicinal extracts for relief of central neuropathic pain from brachial plexus avulsion: results of a randomised controlled trial. Pain 2004; 112(3): 299–36

    PubMed  Article  Google Scholar 

  75. Abrams DI, Jay CA, Shade SB, et al. Cannabis in painful HIV-associated sensory neuropathy: a randomized placebo-controlled trial. Neurology 2007; 68(7): 515–21

    PubMed  Article  CAS  Google Scholar 

  76. Karst M, Salim K, Burstein S, et al. Analgesic effect of the synthetic cannabinoid CT-3 on chronic neuropathic pain: a randomized controlled trial. JAMA 2003; 290(13): 1757–62

    PubMed  Article  CAS  Google Scholar 

  77. Salim K, Schneider U, Burstein S, et al. Pain measurements and side effect profile of the novel cannabinoid ajulemic acid. Neuropharmacology 2005; 48(8): 1164–71

    PubMed  Article  CAS  Google Scholar 

  78. Pinsger M, Schimetta W, Volc D, et al. Benefits of an add-on treatment with the synthetic cannabinomimetic nabilone on patients with chronic pain: a randomized controlled trial. Wien Klin Worchenschr 2006; 118(11–12): 327–35

    Article  Google Scholar 

  79. Zajicek JP, Sanders HP, Wright DE, et al. Cannbinoids and multiple sclerosis (CAMS) study: safety and efficacy data for 12 month follow up. J Neurol Neurosurg Psychiatry 2005; 76: 1664–9

    PubMed  Article  CAS  Google Scholar 

  80. Petersen KL, Rowbotham MC. A new human experimental pain model: the heat/capsaicin sensitization model [published erratum appears in Neuroreport 2002 Jan 21; 13 (1): inside back cover]. Neuroreport 1999; 10(7): 1511–6

    PubMed  Article  CAS  Google Scholar 

  81. Burstein S. Ajulemic acid (IP-751): synthesis, proof of principle, toxicity studies, and clinical trials. AAPS J 2005; 7(1): E143–8

    PubMed  Article  CAS  Google Scholar 

  82. Vann RE, Cook CD, Martin BR, et al. Cannabimimetic properties of ajulemic acid. J Pharmacol Exp Ther 2007; 320(2): 678–86

    PubMed  Article  CAS  Google Scholar 

  83. Crippa JA, Zuardi AW, Garrido GE, et al. Effects of cannabidiol (CBD) on regional cerebral blood flow. Neuropsychopharmacology 2004; 29(2): 417–26

    PubMed  Article  CAS  Google Scholar 

  84. Wade DT, Makela P, Robson P, et al. Do cannabis-based medicinal extracts have general or specific effects on symptoms in multiple sclerosis? A double-blind, randomized, placebo-controlled study on 160 patients. Mult Scler 2004; 10(4): 434–41

    PubMed  Article  CAS  Google Scholar 

  85. Killestein J, Hoogervorst EL, Reif M, et al. Safety, tolerability, and efficacy of orally administered cannabinoids in MS. Neurology 2002; 58(9): 1404–7

    PubMed  Article  CAS  Google Scholar 

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No sources of funding were used to assist in the preparation of this review. The authors have no conflicts of interest that are directly relevant to the content of this review.

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  1. School of Health Sciences, Pharmacology Unit, Rey Juan Carlos University, Madrid, Spain

    M. Isabel Martín Fontelles & Carlos Goicoechea García

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  1. M. Isabel Martín Fontelles
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Correspondence to M. Isabel Martín Fontelles.

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Fontelles, M.I.M., García, C.G. Role of Cannabinoids in the Management of Neuropathic Pain. CNS Drugs 22, 645–653 (2008). https://doi.org/10.2165/00023210-200822080-00003

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Keywords

  • Neuropathic Pain
  • Anandamide
  • Fatty Acid Amide Hydrolase
  • Cannabidiol
  • Chronic Neuropathic Pain